Activity-based protein profiling reveals deubiquitinase and aldehyde dehydrogenase targets of a cyanopyrrolidine probe,RSC Medicinal Chemistry

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Activity-based protein profiling reveals deubiquitinase and aldehyde dehydrogenase targets of a cyanopyrrolidine probe
RSC Medicinal Chemistry ( IF 4.1 ) Pub Date : 2021-08-16 , DOI: 10.1039/d1md00218j
Nattawadee Panyain ₁ , Aurélien Godinat ₁ , Aditya Raymond Thawani ₁ , Sofía Lachiondo-Ortega ₁ , Katie Mason ₂ , Sarah Elkhalifa ₂ , Lisa M Smith ₂ , Jeanine A Harrigan ₂ , Edward W Tate _{1,

3}

Affiliation

Ubiquitin carboxy-terminal hydrolase L1 (UCHL1), a deubiquitinating enzyme (DUB), is a potential drug target in various cancers, and liver and lung fibrosis. However, bona fide functions and substrates of UCHL1 remain poorly understood. Herein, we report the characterization of UCHL1 covalent inhibitor MT16-001 based on a thiazole cyanopyrrolidine scaffold. In combination with chemical proteomics, a closely related activity-based probe (MT16-205) was used to generate a comprehensive quantitative profile for on- and off-targets at endogenous cellular abundance. Both compounds are selective for UCHL1 over other DUBs in intact cells but also engage a range of other targets with good selectivity over the wider proteome, including aldehyde dehydrogenases, redox-sensitive Parkinson's disease related protein PARK7, and glutamine amidotransferase. Taken together, these results underline the importance of robust profiling of activity-based probes as chemical tools and highlight the cyanopyrrolidine warhead as a versatile platform for liganding diverse classes of protein with reactive cysteine residues which can be used for further inhibitor screening, and as a starting point for inhibitor development.

中文翻译：

基于活性的蛋白质分析揭示了氰基吡咯烷探针的去泛素酶和乙醛脱氢酶靶标

泛素羧基末端水解酶 L1 (UCHL1) 是一种去泛素化酶 (DUB)，是多种癌症以及肝纤维化和肺纤维化的潜在药物靶点。然而，UCHL1 的真正功能和底物仍然知之甚少。在此，我们报告了基于噻唑氰基吡咯烷支架的 UCHL1 共价抑制剂MT16-001的表征。与化学蛋白质组学相结合，使用密切相关的基于活性的探针 ( MT16-205 ) 生成内源细胞丰度的靶标和脱靶的全面定量分析。与完整细胞中的其他 DUB 相比，这两种化合物对 UCHL1 的选择性较高，而且还对一系列其他靶标具有良好的选择性，对更广泛的蛋白质组具有良好的选择性，包括醛脱氢酶、氧化还原敏感的帕金森病相关蛋白 PARK7 和谷氨酰胺酰胺转移酶。总而言之，这些结果强调了基于活性的探针作为化学工具的稳健分析的重要性，并强调了氰基吡咯烷弹头作为一种多功能平台，用于将不同类别的蛋白质与反应性半胱氨酸残基配体，可用于进一步的抑制剂筛选，并作为抑制剂开发的起点。

更新日期：2021-09-13

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